PROJECT SUMMARY Bourbon virus is the newest member of a growing group of tick-borne viruses. It was discovered in 2014 in the blood of a 50-year old farmer from Bourbon County, Kansas. He died several weeks later due to multiorgan failure and cardiopulmonary arrest. Additional human cases of Bourbon virus have been identified since then including the most recent fatal case in our hospital in St. Louis, Missouri. Currently, there are no vaccines or therapeutics against this virus. Ticks are important arthropod vectors for spreading viruses from wildlife to humans. To date, at least 40 known viral species are transmitted by ticks, and some of them are a significant threat to human health. Such viruses include tick-borne encephalitis virus, severe fever and thrombocytopenia syndrome virus, and Bourbon virus. Several of these viruses are found predominantly in ticks in the Midwest region of the United States. Apart from the discovery of these viruses, there are no concerted efforts to study these viruses, develop molecular and serological assays, animal models, and most importantly generate therapies that can protect and treat individuals infected with these potentially deadly tick-borne viruses. Thus, there is an urgent need to develop animal models, and validate antiviral therapies that can treat and cure Bourbon virus infected patients. We show for the first time that Bourbon virus replication is inhibited by favipiravir, a broad-spectrum antiviral drug that is approved for clinical use in Japan. Using a new mouse model for Bourbon virus, we subsequently show that favipiravir can prevent fatal disease in vivo. This proposal is aimed at validating the pre-clinical efficacy of favipiravir and related RNA-dependent RNA polymerase inhibitors against Bourbon virus in vivo and establish the seroprevalence of Bourbon virus using high-throughput serological assays and reporter viruses. Successful completion of the proposed studies will lead to the identification of a potential therapy for Bourbon virus and characterization of the disease burden in humans.